Identification of Genetic Subtypes of Diffuse Large B-Cell Lymphoma


Key Points

  • Four distinct genetic subtypes of DLBCL were identified.
  • The subtypes were associated with differences in response to immunochemotherapy.

In a study reported in The New England Journal of Medicine, Schmitz et al identified four subtypes of diffuse large B-cell lymphoma (DLBCLs) with distinct genetic, epigenetic, and clinical characteristics that may be amenable to different therapeutic approaches.

Study Details

The study involved analysis of 574 DLBCL biopsy samples using exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing

of 372 genes to identify genes with recurrent aberrations. An algorithm was developed to identify genetic subtypes based on co-occurrence of genetic alterations.

Genetic Subtypes

Four prominent genetic subtypes were identified, based on co-occurrence of MYD88L265P and CD79B mutations (MCD subtype), BCL6 fusions and NOTCH2 mutations (BN2 subtype), NOTCH1 mutations (N1 subtype), and EZH2 mutations and BCL2 translocations (EZB subtype); it was estimated that these genetic subtypes accounted for 47% of DLBCL cases. Genetic aberrations in multiple genes distinguished each of these genetic subtypes from other DLBCLs, with the subtypes differing phenotypically, as reflected in differences in gene expression signatures and responses to immunochemotherapy. Analysis among 119 patients with tumors in one of the four subtypes who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like chemotherapy showed significant differences across subtypes in progression-free survival (P = 8.88×10-6) and overall survival (P = 1.70×10-4), with better outcomes in the BN2 and EZB subtypes and poorer outcomes in the MCD and N1 subtypes. Estimated 5-year overall survival was 26%, 36%, 65%, and 68% for the MCD, N1, BN2, and EZB subtypes, respectively. Genetic pathway analysis indicated that the MCD and BN2 subtypes may rely on “chronic active” B-cell receptor signaling, presenting a target for therapeutic inhibition.

The investigators concluded, “We uncovered genetic subtypes of DLBCL with distinct genotypic, epigenetic, and clinical characteristics, providing a potential nosology for precision-medicine strategies in DLBCL.”

The study was funded by the Intramural Research Program of the National Institutes of Health and others.

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